ingest cdrApp 2018-06-13T20:55:49.623Z 51cd2fe2-3fd7-401f-a923-a97bc3db68a2 modifyDatastreamByValue RELS-EXT fedoraAdmin 2018-06-13T22:23:54.775Z Setting exclusive relation addDatastream MD_TECHNICAL fedoraAdmin 2018-06-13T22:24:06.357Z Adding technical metadata derived by FITS addDatastream MD_FULL_TEXT fedoraAdmin 2018-06-13T22:24:29.201Z Adding full text metadata extracted by Apache Tika modifyDatastreamByValue RELS-EXT fedoraAdmin 2018-06-13T22:24:51.188Z Setting exclusive relation modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-07-11T01:37:43.574Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-07-17T21:48:35.148Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-08-08T21:00:48.277Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-08-15T18:10:37.506Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-09-21T18:34:39.927Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-09-26T21:41:09.511Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-10-11T22:25:23.599Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2019-03-20T15:56:12.938Z Ricardo Antonia Author Curriculum in Genetics and Molecular Biology School of Medicine IKK FAMILY KINASES REGULATE CELL GROWTH, METABOLISM AND AUTOPHAGY BY PHOSPHORYLATION OF KEY SUBSTRATES Inflammation is now widely accepted to be an essential mediator of the balance between cell growth, metabolism, and autophagy. A group of kinases belonging to the IB kinase (IKK) family has emerged as critical regulators of the interplay between inflammation and energy usage in both healthy and diseased tissues. They accomplish this task by phosphorylation of a variety of protein targets. My dissertation work has focused on two of these phosphorylation targets. In Chapter 2, I characterized the role of IKK in regulating the AMP-activated protein kinase (AMPK), the primary sensor of ATP levels in a cell. I found that IKK directly phosphorylates Thr172 within the AMPK activation loop, both basally in cancer cell lines and in response to cytokine stimulation. Thr172 phosphorylation of AMPK is well-characterized to increase the activity of AMPK and to phosphorylation of downstream AMPK targets. By understanding the mechanism of IKK-mediated AMPK activation, I was able to devise a strategy for exploiting a metabolic weakness of LKB1 deficient lung cancers, which involved combining an IKK inhibitor with the mitochondrial complex I inhibitor phenformin. In Chapter 3, I characterized the mechanism whereby the IKK-related kinase, TANK-binding kinase 1 (TBK1) phosphorylated a critical component of mTORC1, Raptor, which could represent a mechanism whereby TBK1 promotes autophagy. Overall, the work presented here adds to our understanding of the mechanisms of how inflammation can regulate metabolism. Knowledge of these mechanisms will hopefully shed new light on ways to therapeutically restrict the metabolic changes induced by inflammation for therapeutic benefit. Spring 2018 2018 Molecular biology Biology Autophagy, Inflammation, Metabolism eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Genetics and Molecular Biology Albert Baldwin Thesis advisor William Marzluff Thesis advisor Adrienne Cox Thesis advisor Lee Graves Thesis advisor Nathaniel Moorman Thesis advisor text Ricardo Antonia Author Curriculum in Genetics and Molecular Biology School of Medicine IKK FAMILY KINASES REGULATE CELL GROWTH, METABOLISM AND AUTOPHAGY BY PHOSPHORYLATION OF KEY SUBSTRATES Inflammation is now widely accepted to be an essential mediator of the balance between cell growth, metabolism, and autophagy. A group of kinases belonging to the IB kinase (IKK) family has emerged as critical regulators of the interplay between inflammation and energy usage in both healthy and diseased tissues. They accomplish this task by phosphorylation of a variety of protein targets. My dissertation work has focused on two of these phosphorylation targets. In Chapter 2, I characterized the role of IKK in regulating the AMP-activated protein kinase (AMPK), the primary sensor of ATP levels in a cell. I found that IKK directly phosphorylates Thr172 within the AMPK activation loop, both basally in cancer cell lines and in response to cytokine stimulation. Thr172 phosphorylation of AMPK is well-characterized to increase the activity of AMPK and to phosphorylation of downstream AMPK targets. By understanding the mechanism of IKK-mediated AMPK activation, I was able to devise a strategy for exploiting a metabolic weakness of LKB1 deficient lung cancers, which involved combining an IKK inhibitor with the mitochondrial complex I inhibitor phenformin. In Chapter 3, I characterized the mechanism whereby the IKK-related kinase, TANK-binding kinase 1 (TBK1) phosphorylated a critical component of mTORC1, Raptor, which could represent a mechanism whereby TBK1 promotes autophagy. Overall, the work presented here adds to our understanding of the mechanisms of how inflammation can regulate metabolism. Knowledge of these mechanisms will hopefully shed new light on ways to therapeutically restrict the metabolic changes induced by inflammation for therapeutic benefit. Spring 2018 2018 Molecular biology Biology Autophagy, Inflammation, Metabolism eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Genetics and Molecular Biology Albert Baldwin Thesis advisor William Marzluff Thesis advisor Adrienne Cox Thesis advisor Lee Graves Thesis advisor Nathaniel Moorman Thesis advisor text Ricardo Antonia Author Curriculum in Genetics and Molecular Biology School of Medicine IKK FAMILY KINASES REGULATE CELL GROWTH, METABOLISM AND AUTOPHAGY BY PHOSPHORYLATION OF KEY SUBSTRATES Inflammation is now widely accepted to be an essential mediator of the balance between cell growth, metabolism, and autophagy. A group of kinases belonging to the IB kinase (IKK) family has emerged as critical regulators of the interplay between inflammation and energy usage in both healthy and diseased tissues. They accomplish this task by phosphorylation of a variety of protein targets. My dissertation work has focused on two of these phosphorylation targets. In Chapter 2, I characterized the role of IKK in regulating the AMP-activated protein kinase (AMPK), the primary sensor of ATP levels in a cell. I found that IKK directly phosphorylates Thr172 within the AMPK activation loop, both basally in cancer cell lines and in response to cytokine stimulation. Thr172 phosphorylation of AMPK is well-characterized to increase the activity of AMPK and to phosphorylation of downstream AMPK targets. By understanding the mechanism of IKK-mediated AMPK activation, I was able to devise a strategy for exploiting a metabolic weakness of LKB1 deficient lung cancers, which involved combining an IKK inhibitor with the mitochondrial complex I inhibitor phenformin. In Chapter 3, I characterized the mechanism whereby the IKK-related kinase, TANK-binding kinase 1 (TBK1) phosphorylated a critical component of mTORC1, Raptor, which could represent a mechanism whereby TBK1 promotes autophagy. Overall, the work presented here adds to our understanding of the mechanisms of how inflammation can regulate metabolism. Knowledge of these mechanisms will hopefully shed new light on ways to therapeutically restrict the metabolic changes induced by inflammation for therapeutic benefit. Spring 2018 2018 Molecular biology Biology Autophagy, Inflammation, Metabolism eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Genetics and Molecular Biology Albert Baldwin Thesis advisor William Marzluff Thesis advisor Adrienne Cox Thesis advisor Lee Graves Thesis advisor Nathaniel Moorman Thesis advisor text Ricardo Antonia Author Curriculum in Genetics and Molecular Biology School of Medicine IKK FAMILY KINASES REGULATE CELL GROWTH, METABOLISM AND AUTOPHAGY BY PHOSPHORYLATION OF KEY SUBSTRATES Inflammation is now widely accepted to be an essential mediator of the balance between cell growth, metabolism, and autophagy. A group of kinases belonging to the IB kinase (IKK) family has emerged as critical regulators of the interplay between inflammation and energy usage in both healthy and diseased tissues. They accomplish this task by phosphorylation of a variety of protein targets. My dissertation work has focused on two of these phosphorylation targets. In Chapter 2, I characterized the role of IKK in regulating the AMP-activated protein kinase (AMPK), the primary sensor of ATP levels in a cell. I found that IKK directly phosphorylates Thr172 within the AMPK activation loop, both basally in cancer cell lines and in response to cytokine stimulation. Thr172 phosphorylation of AMPK is well-characterized to increase the activity of AMPK and to phosphorylation of downstream AMPK targets. By understanding the mechanism of IKK-mediated AMPK activation, I was able to devise a strategy for exploiting a metabolic weakness of LKB1 deficient lung cancers, which involved combining an IKK inhibitor with the mitochondrial complex I inhibitor phenformin. In Chapter 3, I characterized the mechanism whereby the IKK-related kinase, TANK-binding kinase 1 (TBK1) phosphorylated a critical component of mTORC1, Raptor, which could represent a mechanism whereby TBK1 promotes autophagy. Overall, the work presented here adds to our understanding of the mechanisms of how inflammation can regulate metabolism. Knowledge of these mechanisms will hopefully shed new light on ways to therapeutically restrict the metabolic changes induced by inflammation for therapeutic benefit. Spring 2018 2018 Molecular biology Biology Autophagy, Inflammation, Metabolism eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Genetics and Molecular Biology Albert Baldwin Thesis advisor William Marzluff Thesis advisor Adrienne Cox Thesis advisor Lee Graves Thesis advisor Nathaniel Moorman Thesis advisor text Ricardo Antonia Author Curriculum in Genetics and Molecular Biology School of Medicine IKK FAMILY KINASES REGULATE CELL GROWTH, METABOLISM AND AUTOPHAGY BY PHOSPHORYLATION OF KEY SUBSTRATES Inflammation is now widely accepted to be an essential mediator of the balance between cell growth, metabolism, and autophagy. A group of kinases belonging to the IB kinase (IKK) family has emerged as critical regulators of the interplay between inflammation and energy usage in both healthy and diseased tissues. They accomplish this task by phosphorylation of a variety of protein targets. My dissertation work has focused on two of these phosphorylation targets. In Chapter 2, I characterized the role of IKK in regulating the AMP-activated protein kinase (AMPK), the primary sensor of ATP levels in a cell. I found that IKK directly phosphorylates Thr172 within the AMPK activation loop, both basally in cancer cell lines and in response to cytokine stimulation. Thr172 phosphorylation of AMPK is well-characterized to increase the activity of AMPK and to phosphorylation of downstream AMPK targets. By understanding the mechanism of IKK-mediated AMPK activation, I was able to devise a strategy for exploiting a metabolic weakness of LKB1 deficient lung cancers, which involved combining an IKK inhibitor with the mitochondrial complex I inhibitor phenformin. In Chapter 3, I characterized the mechanism whereby the IKK-related kinase, TANK-binding kinase 1 (TBK1) phosphorylated a critical component of mTORC1, Raptor, which could represent a mechanism whereby TBK1 promotes autophagy. Overall, the work presented here adds to our understanding of the mechanisms of how inflammation can regulate metabolism. Knowledge of these mechanisms will hopefully shed new light on ways to therapeutically restrict the metabolic changes induced by inflammation for therapeutic benefit. Spring 2018 2018 Molecular biology Biology Autophagy, Inflammation, Metabolism eng Doctor of Philosophy Dissertation Genetics and Molecular Biology Albert Baldwin Thesis advisor William Marzluff Thesis advisor Adrienne Cox Thesis advisor Lee Graves Thesis advisor Nathaniel Moorman Thesis advisor text University of North Carolina at Chapel Hill Degree granting institution Ricardo Antonia Author Curriculum in Genetics and Molecular Biology School of Medicine IKK FAMILY KINASES REGULATE CELL GROWTH, METABOLISM AND AUTOPHAGY BY PHOSPHORYLATION OF KEY SUBSTRATES Inflammation is now widely accepted to be an essential mediator of the balance between cell growth, metabolism, and autophagy. A group of kinases belonging to the IB kinase (IKK) family has emerged as critical regulators of the interplay between inflammation and energy usage in both healthy and diseased tissues. They accomplish this task by phosphorylation of a variety of protein targets. My dissertation work has focused on two of these phosphorylation targets. In Chapter 2, I characterized the role of IKK in regulating the AMP-activated protein kinase (AMPK), the primary sensor of ATP levels in a cell. I found that IKK directly phosphorylates Thr172 within the AMPK activation loop, both basally in cancer cell lines and in response to cytokine stimulation. Thr172 phosphorylation of AMPK is well-characterized to increase the activity of AMPK and to phosphorylation of downstream AMPK targets. By understanding the mechanism of IKK-mediated AMPK activation, I was able to devise a strategy for exploiting a metabolic weakness of LKB1 deficient lung cancers, which involved combining an IKK inhibitor with the mitochondrial complex I inhibitor phenformin. In Chapter 3, I characterized the mechanism whereby the IKK-related kinase, TANK-binding kinase 1 (TBK1) phosphorylated a critical component of mTORC1, Raptor, which could represent a mechanism whereby TBK1 promotes autophagy. Overall, the work presented here adds to our understanding of the mechanisms of how inflammation can regulate metabolism. Knowledge of these mechanisms will hopefully shed new light on ways to therapeutically restrict the metabolic changes induced by inflammation for therapeutic benefit. Spring 2018 2018 Molecular biology Biology Autophagy, Inflammation, Metabolism eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Genetics and Molecular Biology Albert Baldwin Thesis advisor William Marzluff Thesis advisor Adrienne Cox Thesis advisor Lee Graves Thesis advisor Nathaniel Moorman Thesis advisor text Ricardo Antonia Creator Curriculum in Genetics and Molecular Biology School of Medicine IKK FAMILY KINASES REGULATE CELL GROWTH, METABOLISM AND AUTOPHAGY BY PHOSPHORYLATION OF KEY SUBSTRATES Inflammation is now widely accepted to be an essential mediator of the balance between cell growth, metabolism, and autophagy. A group of kinases belonging to the IB kinase (IKK) family has emerged as critical regulators of the interplay between inflammation and energy usage in both healthy and diseased tissues. They accomplish this task by phosphorylation of a variety of protein targets. My dissertation work has focused on two of these phosphorylation targets. In Chapter 2, I characterized the role of IKK in regulating the AMP-activated protein kinase (AMPK), the primary sensor of ATP levels in a cell. I found that IKK directly phosphorylates Thr172 within the AMPK activation loop, both basally in cancer cell lines and in response to cytokine stimulation. Thr172 phosphorylation of AMPK is well-characterized to increase the activity of AMPK and to phosphorylation of downstream AMPK targets. By understanding the mechanism of IKK-mediated AMPK activation, I was able to devise a strategy for exploiting a metabolic weakness of LKB1 deficient lung cancers, which involved combining an IKK inhibitor with the mitochondrial complex I inhibitor phenformin. In Chapter 3, I characterized the mechanism whereby the IKK-related kinase, TANK-binding kinase 1 (TBK1) phosphorylated a critical component of mTORC1, Raptor, which could represent a mechanism whereby TBK1 promotes autophagy. Overall, the work presented here adds to our understanding of the mechanisms of how inflammation can regulate metabolism. Knowledge of these mechanisms will hopefully shed new light on ways to therapeutically restrict the metabolic changes induced by inflammation for therapeutic benefit. Molecular biology Biology Autophagy; Inflammation; Metabolism eng Doctor of Philosophy Dissertation Genetics and Molecular Biology Albert Baldwin Thesis advisor William Marzluff Thesis advisor Adrienne Cox Thesis advisor Lee Graves Thesis advisor Nathaniel Moorman Thesis advisor text University of North Carolina at Chapel Hill Degree granting institution 2018 2018-05 Ricardo Antonia Author Curriculum in Genetics and Molecular Biology School of Medicine IKK FAMILY KINASES REGULATE CELL GROWTH, METABOLISM AND AUTOPHAGY BY PHOSPHORYLATION OF KEY SUBSTRATES Inflammation is now widely accepted to be an essential mediator of the balance between cell growth, metabolism, and autophagy. A group of kinases belonging to the IB kinase (IKK) family has emerged as critical regulators of the interplay between inflammation and energy usage in both healthy and diseased tissues. They accomplish this task by phosphorylation of a variety of protein targets. My dissertation work has focused on two of these phosphorylation targets. In Chapter 2, I characterized the role of IKK in regulating the AMP-activated protein kinase (AMPK), the primary sensor of ATP levels in a cell. I found that IKK directly phosphorylates Thr172 within the AMPK activation loop, both basally in cancer cell lines and in response to cytokine stimulation. Thr172 phosphorylation of AMPK is well-characterized to increase the activity of AMPK and to phosphorylation of downstream AMPK targets. By understanding the mechanism of IKK-mediated AMPK activation, I was able to devise a strategy for exploiting a metabolic weakness of LKB1 deficient lung cancers, which involved combining an IKK inhibitor with the mitochondrial complex I inhibitor phenformin. In Chapter 3, I characterized the mechanism whereby the IKK-related kinase, TANK-binding kinase 1 (TBK1) phosphorylated a critical component of mTORC1, Raptor, which could represent a mechanism whereby TBK1 promotes autophagy. Overall, the work presented here adds to our understanding of the mechanisms of how inflammation can regulate metabolism. Knowledge of these mechanisms will hopefully shed new light on ways to therapeutically restrict the metabolic changes induced by inflammation for therapeutic benefit. Spring 2018 2018 Molecular biology Biology Autophagy, Inflammation, Metabolism eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Genetics and Molecular Biology Albert Baldwin Thesis advisor William Marzluff Thesis advisor Adrienne Cox Thesis advisor Lee Graves Thesis advisor Nathaniel Moorman Thesis advisor text Ricardo Antonia Creator Curriculum in Genetics and Molecular Biology School of Medicine Inflammation is now widely accepted to be an essential mediator of the balance between cell growth, metabolism, and autophagy. A group of kinases belonging to the IB kinase (IKK) family has emerged as critical regulators of the interplay between inflammation and energy usage in both healthy and diseased tissues. They accomplish this task by phosphorylation of a variety of protein targets. My dissertation work has focused on two of these phosphorylation targets. In Chapter 2, I characterized the role of IKK in regulating the AMP-activated protein kinase (AMPK), the primary sensor of ATP levels in a cell. I found that IKK directly phosphorylates Thr172 within the AMPK activation loop, both basally in cancer cell lines and in response to cytokine stimulation. Thr172 phosphorylation of AMPK is well-characterized to increase the activity of AMPK and to phosphorylation of downstream AMPK targets. By understanding the mechanism of IKK-mediated AMPK activation, I was able to devise a strategy for exploiting a metabolic weakness of LKB1 deficient lung cancers, which involved combining an IKK inhibitor with the mitochondrial complex I inhibitor phenformin. In Chapter 3, I characterized the mechanism whereby the IKK-related kinase, TANK-binding kinase 1 (TBK1) phosphorylated a critical component of mTORC1, Raptor, which could represent a mechanism whereby TBK1 promotes autophagy. Overall, the work presented here adds to our understanding of the mechanisms of how inflammation can regulate metabolism. Knowledge of these mechanisms will hopefully shed new light on ways to therapeutically restrict the metabolic changes induced by inflammation for therapeutic benefit. 2018-05 2018 Molecular biology Biology Autophagy; Inflammation; Metabolism eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Albert Baldwin Thesis advisor William Marzluff Thesis advisor Adrienne Cox Thesis advisor Lee Graves Thesis advisor Nathaniel Moorman Thesis advisor text Antonia_unc_0153D_17793.pdf uuid:0e61021b-ed07-4dcf-8b65-46fec37df26f 2020-06-13T00:00:00 2018-05-03T14:42:04Z proquest application/pdf 5808421